+

WO2013013609A1 - Formes polymorphes de composés en tant qu'inhibiteur de prolyle hydroxylase et leurs utilisations - Google Patents

Formes polymorphes de composés en tant qu'inhibiteur de prolyle hydroxylase et leurs utilisations Download PDF

Info

Publication number
WO2013013609A1
WO2013013609A1 PCT/CN2012/079058 CN2012079058W WO2013013609A1 WO 2013013609 A1 WO2013013609 A1 WO 2013013609A1 CN 2012079058 W CN2012079058 W CN 2012079058W WO 2013013609 A1 WO2013013609 A1 WO 2013013609A1
Authority
WO
WIPO (PCT)
Prior art keywords
polymorph
compound
ray powder
diffraction pattern
powder diffraction
Prior art date
Application number
PCT/CN2012/079058
Other languages
English (en)
Inventor
Xinshan Kang
Wei LONG
Jianxi ZHANG
Yunyan Hu
Yinxiang Wang
Original Assignee
Zhejiang Beta Pharma Incorporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhejiang Beta Pharma Incorporation filed Critical Zhejiang Beta Pharma Incorporation
Priority to US14/233,902 priority Critical patent/US9206134B2/en
Priority to EP12817360.6A priority patent/EP2734504B1/fr
Priority to JP2014520521A priority patent/JP6099644B2/ja
Priority to CA2842730A priority patent/CA2842730C/fr
Priority to KR1020147004452A priority patent/KR102029951B1/ko
Priority to ES12817360.6T priority patent/ES2606631T3/es
Priority to AU2012289429A priority patent/AU2012289429B2/en
Priority to CN201280036322.0A priority patent/CN104024227B/zh
Publication of WO2013013609A1 publication Critical patent/WO2013013609A1/fr
Priority to IL230580A priority patent/IL230580B/en
Priority to ZA2014/01310A priority patent/ZA201401310B/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to the polymorphic forms of a novel compound, and their use in inhibiting prolyl hydroxylase activity.
  • the present invention also relates to a method of using at least one of the polymorphs thereof in modulating HIF level or activity, treating a disease, a disorder or a condition associated with increasing or lowing HIF level or activity, in a subject.
  • HIF Hemoxia Inducible Factor
  • the cellular transcription factor HIF occupies a central position in oxygen homeostasis in a wide range of organisms and is a key regulator of responses to hypoxia.
  • the genes regulated by HIF transcriptional activity can play critical roles in angiogenesis, erythropoiesis, hemoglobin F production, energy metabolism, inflammation, vasomotor function, apoptosis and cellular proliferation.
  • HIF can also play a role in cancer, in which it is commonly upregulated, and in the physiological responses to ischemia and hypoxia.
  • HIF- ⁇ is a constitutive nuclear protein that dimerizes with oxygen-regulated HIF-a subunits. Oxygen regulation occurs through hydroxylation of the HIF-a subunits, which are then rapidly destroyed by the proteasome.
  • pVHL protein von Hippel-Lindau tumor suppressor protein
  • pVHL protein binds to hydroxylated HIF-subunits, thereby promoting their ubiquitin dependent proteolysis. This process is suppressed under hypoxic conditions, stabilizing HIF-a and promoting the transcription and activation of the HIFaP dimer.
  • HIF-a subunits can occur on proline and asparagine residues and can be catalyzed by a family of 2-oxoglutarate dependent enzymes.
  • This family includes the HIF prolyl hydroxylase isozymes (PHDs), which hydroxylate Pro 402 and Pro 564 of human HIFla, as well as Factor Inhibiting HIF (FIH), which hydroxylates Asn 803 of human HIFl . Inhibition of FIH or the PHDs leads to HIF stabilization and further transcription and activation.
  • PHDs HIF prolyl hydroxylase isozymes
  • FIH Factor Inhibiting HIF
  • Inhibition of FIH or the PHDs leads to HIF stabilization and further transcription and activation.
  • the present invention relates to approximately pure crystalline polymorphs, wherein these polymorphs are the polymorphs of the compound of Formula I, and/or a hydrate thereof, and/or a solvate thereof.
  • the compound of Formula I of the present invention exists in one or more crystal forms.
  • the inventors designated these crystal forms Form I, Form II, Form III, Form IV, Form V, Form VI and Form VII.
  • the present invention provides a crystalline polymorph of the compound of Formula I that exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 ⁇ of approximately 5.9°, 11.0° and 25.9°.
  • the present invention further provides preferred embodiments of the crystalline polymorph.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 14.9A, 8.0A and 3.4A.
  • the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 5.9°, 11.0°, 17.6°, 22.6°, 25.9° and 26.9°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 14.9A, 8.0A, 5.lA, 3.9A, 3.4A and 3.3 A.
  • the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 5.9°, 11.0°, 14.8°, 17.6°, 22.6°, 24.0°, 25.9° and 26.9°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 14.9A, 8.0A, 6.0A, 5.1 A, 3.9A, 3.7A, 3.4A and 3.3A.
  • the X-ray powder diffraction pattern is shown as in Figure 1.
  • the polymorph has a melting point of 174-177 °C.
  • the polymorph has a purity of >85%.
  • the polymorph has a purity of >95%.
  • the polymorph has a purity of >99%.
  • the present also provides a method of preparing the crystalline polymorph, comprising the steps of dissolving the compound of Formula I as prepared in Example 1 in the mixed solvent of methanol/MTBE ( methyl tertbutyl ether ) at room temperature, followed by a spontaneous precipitation, and recovering the resulted crystalline polymorph.
  • methanol/MTBE methyl tertbutyl ether
  • the present invention also provides a crystalline polymorph of the compound of Formula I that exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 ⁇ of approximately 8.2°, 14.5° and 26.6°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 10.8 A, 6.1 A and 3.4 A.
  • the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.2°, 13.3°, 14.5°, 21.2° and 26.6°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 10.8A, 6.7A, 6.lA, 4.2A and 3.4A.
  • the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.2°, 9.6°, 13.3°, 14.5°, 21.2°, 22.8°, 25.4° and 26.6°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 10.8A, 9.3A, 6.7A, 6.1 A, 4.2A, 3.9A, 3.5A and 3.4A.
  • the X-ray powder diffraction pattern is shown as in Figure 2.
  • the polymorph has a melting point of 209-212 °C
  • the polymorph has a purity of >85%.
  • the polymorph has a purity of >95%.
  • the polymorph has a purity of >99%.
  • the present invention also provides a method of preparing the crystalline polymorph comprising the steps of slurrying excess amount of the compound of Formula I as prepared in from Example 1 in the mixed solvent of H 2 0/acetonitrile (3: 1), or H 2 0/ethanol at room temperature or 50 °C, or in methanol/H 2 0 at RT for at least 48 hrs. court and recovering the resulted crystalline polymorph.
  • the present invention further provides a crystalline polymorph of the compound of Formula I that exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 ⁇ of approximately 6.2°, 17.8° and 26.2°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 14.3A, 5.0A and 3.4A.
  • the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 6.2°, 17.8°, 22.0°, 26.2° and 26.9°.
  • the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 6.2°, 12.1°, 15.6°, 17.8°, 22.0°, 26.2°, 26.9° and 28.9°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 14.3A, 7.3A, 5.7A, 5.0A, 4.0A, 3.4A, 3.3A and 3.lA.
  • the polymorph has a purity of >85%.
  • the polymorph has a purity of >95%.
  • the polymorph has a purity of >99%.
  • the X-ray powder diffraction pattern is shown as in Figure 3.
  • the polymorph has a melting point of 198-200 ° C .
  • the present also provides a method of preparing the crystalline polymorph, comprising the steps of: dissolving the compound of Formula I as prepared in Example 1 in the mixed solvent of methanol/acetonitrile at room temperature, followed by a spontaneous precipitation, and recovering the resulted crystalline polymorpli;or,comprising the steps of slurrying excess amount of the compound of Formula I as prepared in from Example 1 in H 2 0, CH 2 C1 2 , IPAc (Isopropyl Acetate), EtOAc, or IPAc/heptane at 50 °C for at least 48 lirs. , and recovering the resulted crystalline polymorph.
  • IPAc Isopropyl Acetate
  • EtOAc EtOAc
  • IPAc/heptane at 50 °C for at least 48 lirs.
  • the present invention further provides a crystalline polymorph of the compound of Formula I that exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 ⁇ of approximately 12.4°, 20.3° and 26.6°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 7.1 A, 4.4A and 3.4A.
  • the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 11.3°, 12.4°, 20.3°, 21.4° and 26.6°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 1.9k, 7.1 A, 4.4A, 4.1 A and 3.4A.
  • the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 11.3°, 12.4°, 15.0°, 17.9°, 20.3°, 21.4°, 24.8° and 26.6°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 7.9A, 7.1 A, 5.9A, 5.0A, 4.4A, 4.1 A, 3.6A and 3.4A.
  • the X-ray powder diffraction pattern is shown as in Figure 4.
  • the polymorph has a melting point of 204-207 °C.
  • the polymorph has a purity of >85%.
  • the polymorph has a purity of >95%.
  • the polymorph has a purity of >99%.
  • the present invention also provides a method of preparing the crystalline polymorph comprising the steps of: slurrying excess amount of the compound of Formula I as prepared in Example 1 in MTBE, the mixed solvent of Isopropyl Acetate/heptane or ethyl acetate/heptane at room temperature for at least 48 hrs.
  • the present invention further provides a crystalline polymorph of the compound of Formula I that exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 ⁇ of approximately 6.0°, 11.1° and 24. ⁇ .
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 14.8A, 8.0A and 3.7A.
  • the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 6.0°, 11. F, 17.7°, 24. ⁇ and 26.9°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 14.8A, 8.0A, 5.0A, 3.7A and 3.3A.
  • the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 6.0°, 8.8°, 11. F, 11.9°, 14.9°, 17.7°, 24.1° and 26.9°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 14.8A, ⁇ . ⁇ , 8.0A, 7.4A, 6.0A, 5.0A, 3.7A and 3.3A.
  • the X-ray powder diffraction pattern is shown as in Figure 5.
  • the polymorph has a melting point of 190-193 ° C
  • the polymorph has a purity of >85%.
  • the polymorph has a purity of >95%.
  • the polymorph has a purity of >99%.
  • the present invention also provides a method of preparing the crystalline polymorph comprising the steps of slurrying excess amount of the compound of Formula I as prepared in from Example 1 in the mixed solvent of MTBE/ ' heptaiie at 50 " C for at least 48 hrs. , and recovering the resulted crystalline polymorph;
  • the present invention further provides a crystalline polymorph of the compound of Formula I that exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 ⁇ of approximately 7. ⁇ , 22.2° and 26.9°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 12.4A, 4.0A and 3.3A.
  • the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 7. ⁇ , 10.6°, 18.8°, 22.2° and 26.9°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 12.4A, 8.4A, 4.7 A, 4.0A and 3.3A.
  • the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 7. ⁇ , 9.4°, 10.6°, 16.5°, 18.8°, 21.3°, 22.2° and 26.9°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 12.4A, 9.4A, 8.4A, 5.4A, 4.7A, 4.2A, 4.0A and 3.3A.
  • the X-ray powder diffraction pattern is shown as in Figure 6.
  • the polymorph has a melting point of 200-203 ° C
  • the polymorph has a purity of >85%.
  • the polymorph has a purity of >95%.
  • the polymorph has a purity of >99%.
  • the present invention also provides a method of preparing the crystalline polymorph comprising the steps of: slurrying excess amount of the compound of Formula I as prepared in the method of Example 1 in the mixed solvent of acetonitrile/f ⁇ O (1 : 1) or THF/H 2 O at room temperature for at least 48 hrs, and recovering the resulted crystalline polymorph;
  • the present invention further provides a crystalline polymorph of the compound of Formula I that exhibits an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 ⁇ of approximately 6.9°, 11.7° and 21.1°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 12.8A, 7.5A and 4.2A.
  • the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 6.9°, 11.7°, 15.1°, 21.1° and 25.8°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 12.8A, 7.5A, 5.9 A, 4.2A and 3.5A.
  • the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 ⁇ of approximately 6.9°, 7.5°, 11.7°, 15.1°, 19.3°, 21. ⁇ , 22.6° and 25.8°.
  • the X-ray powder diffraction pattern has characteristic peaks, expressed in terms of the interplanar distance, at 12.8A, 11.8A, 7.5A, 5.9A, 4.6A, 4.2A, 3.9A and 3.5A..
  • the X-ray powder diffraction pattern is shown as in Figure 7.
  • the polymorph has a purity of >85%.
  • the polymorph has a purity of >95%.
  • the polymorph has a purity of >99%.
  • the present invention further provides a method of preparing the crystalline polymorph comprising the steps of heating the Crystalline Form VI as prepared in Example 7 to 180 °C, and recovering the resulted crystalline polymorph.
  • the present invention further provides the use of these crystalline polymorphs.
  • a pharmaceutical composition comprises a therapeutically effective amount of crystalline polymorphs of the present invention, and a pharmaceutically acceptable excipient adjuvant or earner.
  • the present invention also provides preferable embodiments of the pharmaceutical composition.
  • the pharmaceutical composition comprises a therapeutically effective amount of a crystalline polymorph of the present invention, in combination with at least one of additional active ingredient.
  • the pharmaceutical composition is used in an oral administration.
  • the pharmaceutical composition is used in tablets or capsules.
  • the pharmaceutical composition comprises 1 wt%-99 wt% of the crystalline polymorph of the present invention.
  • the pharmaceutical composition comprises 1 wt%-70 wt% of the crystalline polymorph of the present invention.
  • the pharmaceutical composition comprises 10 wt%-30 wt% of the crystalline polymorph of the present invention.
  • the crystalline polymorphs of the present invention can be used in manufacturing a medicament for modulating HIF level or HIF activity in a subject.
  • the present invention also provides preferable embodiments of the uses of the crystalline polymorphs.
  • the crystalline polymorphs of the present invention can be used in manufacturing a medicament for the treatment of a disease, a disorder, or a condition associated with HIF level or HIF activity.
  • the crystalline polymorphs of the present invention can be used in manufacturing a medicament for the treatment of ischemia, anemia, or a disease, disorder, or condition associated with ischemia or anemia.
  • the crystalline polymorphs of the present invention can be used in manufacturing a medicament for the treatment of a disease, a disorder, or a condition selected from ischemia, anemia, wound healing, auto-transplantation, allo-transplantation, xeno-transplantation, systemic high blood pressure, thalassemia, diabetes, cancer or an inflammatory disorder, or a combination of two or more thereof, in a subject.
  • a method for treating a disease, a disorder, or a condition associated with HIF level or HIF activity in a subject by administering to the subject one crystalline polymorph of the present invention.
  • ischemia anemia, or a disease, a disorder or a condition associated with ischemia or anemia in a subject by administering to the subject one crystalline polymorph of the present invention.
  • substantially pure refers to at least 85 wt%, preferably at least 95 wt%, more preferably at least 99 wt% of the compound of Formula I exists in a crystal form of the present invention, particularly in the crystal forms of Form I, Form II, Form III, Form IV, Form V, Form VI or Form VII.
  • the X-ray powder diffraction pattern shown as in Figure 1 refers to the X-ray powder diffraction pattern that show major peaks as in Figure 1, wherein major peaks refer to those with the relative intensity greater than 10%, preferably greater than 30%, relative to the highest peak (with its relative intensity designated to be 100%) in Figure 1.
  • the X-ray powder diffraction pattern shown as in Figure 2, 3, 4, 5, 6 or 7 refers to the X-ray powder diffraction pattern that show major peaks as in Figure 2, 3, 4, 5, 6 or 7, wherein major peaks refer to those with the relative intensity greater than 10%, preferably greater than 30%, relative to the highest peak (with its relative intensity designated to be 100%) in Figure 2, 3, 4, 5, 6 or 7, respectively.
  • the present invention also provides a method of preparing the compound of Formula I, as follows,
  • the present invention also provides a method of preparing Crystalline Form I, Crystalline Form II, Crystalline Form III, Crystalline Form IV, Crystalline Form V, Crystalline Form VI or Crystalline Form VII of the compound of Formula I..Crystallizing the compound of the present invention from a suitable solvent system comprising at least one solvent, can be achieved by methods of spontaneous precipitation (evaporation), cooling, and/or adding anti-solvent (in which the compound of the present invention has relatively lower solubility), in order to achieve oversaturation in solvent system.
  • Crystallization also cars be achieved by using or not using crystal seeds that is suitable for crystallizing the compound of the present invention.
  • the present invention further provides a pharmaceutical composition, comprising a therapeutically effective amount of one or more crystalline polymorphs of Crystalline Form I, Crystalline Form II, Crystalline Form III, Crystalline Form IV, Crystalline Form V, Crystalline Form VI or Crystalline Form VII of the compound of Formula I, and a pharmaceutically acceptable excipient, adjuvant or carrier.
  • the pharmaceutical composition contains 1 wt%-99 wt%, preferably 1 wi.%-70 wt%, more preferably 10 wt%-30 wt% of any one crystalline polymorph of Crystalline Form I, Crystalline Form II, Crystalline Form III, Crystalline Form IV, Crystalline Form V Crystalline Form VI or Crystalline Form VII of the compound of Formula I.
  • the present invention also provides the use of the compound of Formula I, or a crystalline polymorph selected from Crystalline Form I, Crystalline Form II, Crystalline Form III, Crystalline Form IV, Crystalline Form V, Crystalline Form VI and Crystalline Form VII thereof, in manufacturing a medicament for modulating HIF level or HIF activity.
  • the present invention also provides a use of the compound of Formula I, or a crystalline polymorph selected from Crystalline Form I, Crystalline Form II, Crystalline Form III, Crystalline Form IV, Crystalline Form V, Crystalline Form VI and Crystalline Form VII thereof, in manufacturing a medicament for the treatment of ischemia, anemia, or a disease, disorder or condition associated with ischemia or anemia.
  • the present invention also provides a use of the compound of Formula I, or a crystalline polymorph selected from Crystalline Form I, Crystalline Form II, Crystalline Form III, Crystalline Form IV, Crystalline Form V, Crystalline Form VI and Crystalline Form VII thereof, in manufacturing a medicament for the treatment of a disease, disorder, or condition selected from ischemia, anemia, wound healing, auto-transplantation, allo-transplantation, xeno-transplantation, systemic high blood pressure, thalassemia, diabetes, cancer or an inflammatory disorder, or a combination of two or more thereof.
  • a disease, disorder, or condition selected from ischemia, anemia, wound healing, auto-transplantation, allo-transplantation, xeno-transplantation, systemic high blood pressure, thalassemia, diabetes, cancer or an inflammatory disorder, or a combination of two or more thereof.
  • terapéuticaally effective amount refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom.
  • the "therapeutically effective amount” can vary with the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments.
  • the "therapeutically effective amount refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.
  • the pharmaceutical composition comprising the compound of the present invention can be administrated via oral, inhalation, rectal, parenteral or topical administration to a subject who needs treatment.
  • the pharmaceutical composition may be a regular solid formulation such as tablets, powder, granule, capsules and the like, a liquid formulation such as water or oil suspension or other liquid formulation such as syrup, solution, suspension or the like; for parenteral administration, the pharmaceutical composition may be solution, water solution, oil suspension concentrate, lyophilized powder or the like.
  • the formulation of the pharmaceutical composition is selected from tablet, coated tablet, capsule, suppository, nasal spray or injection, more preferably tablet or capsule.
  • the pharmaceutical composition can be a single unit administration with an accurate dosage.
  • the pharmaceutical composition may further comprise additional active ingredients.
  • compositions of the present invention can be produced by the conventional methods in the pharmaceutical field.
  • the active ingredient can be mixed with one or more excipients, then to make the desired formulation.
  • the "pharmaceutically acceptable carrier” refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, for example: a diluent, a vehicle such as water, various organic solvents, etc, a filler such as starch, sucrose, etc; a binder such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone (PVP ) ; a wetting agent such as glycerol; a disintegrating agent such as agar, calcium carbonate and sodium bicarbonate; an absorption enhancer such as quaternary ammonium compound; a surfactant such as hexadecanol; an absorption carrier such as Kaolin and soap clay; a lubricant such, as talc, calcium, stearate, magnesium stearate, polyethylene glycol, etc.
  • the pharmaceutical composition further comprises other pharmaceutically acceptable excipients such as a decentralized agent, a stabi lizer, a thickener, a compiexing agent, a buffering agent, a permeation enhancer, a polymer, aromatics, a sweetener, and a dye.
  • excipient is suitable for desired formulation and administration type.
  • the term "disease” or “disorder” or “condition” refers to any disease, discomfort, illness, symptoms or indications.
  • Figure 1 shows the X-ray powder diffraction pattern of Crystalline Form I of the compound of Formula I
  • Figure 2 shows the X-ray powder diffraction pattern of Crystalline Form II of the compound of Formula I
  • Figure 3 shows the X-ray powder diffraction pattern of Crystalline Form III of the compound of Formula I
  • Figure 4 shows the X-ray powder diffraction pattern of Crystalline Form IV of the compound of Formula I
  • Figure 5 shows the X-ray powder diffraction pattern of Crystalline Form V of the compound of Formula I
  • Figure 6 shows the X-ray powder diffraction pattern of Crystalline Form VI of the compound of Formula I
  • Figure 7 shows the X-ray powder diffraction pattern of Crystalline Form VII of the compound of Formula I
  • the X-ray powder diffraction (XRPD) patterns shown as in Figure 1, 2, 3, 4, 5, 6 and 7 were generated on a PANalytical X-ray Diffraction System with Empyrean console.
  • the diffraction peak positions were calibrated by single crystal silicon which has a 2 ⁇ value of 28.443 degree.
  • the K- Alpha radiation of an Empyrean Cu LEF X-ray tube was used as the light source of the X-ray.
  • Example 4 a slurry suspension of excess amount of the Crystalline Form III as prepared in Example 4 was stirred in the mixed solvent of FFiO/acetone at 50 ° C for 12-14 days, to obtain the desired Crystalline Form IV, with the melting point of 204-207 ° C .
  • Ciystalline Form V prepared from the method of Example 6 was heated to 180 °C, to obtain the desired Crystalline Form VH.
  • HIF-PHD2 activity was measured using homogeneous TR-FRET technology (see also, US2008/004817; Dao JH et al., Anal Biochem. 2009, 384:213-23).
  • DMSO solution of test compound To each well of a l/2Area 96-well plate was added 2 ⁇ . DMSO solution of test compound and 40 ⁇ . of assay buffer (50 mM Tris PH7.4/0.01% Tween-20/0.1 mg/ml BSA/1 mM Sodium ascorbate/20 ug/ml Catalase/10 ⁇ FeS04) containing 600 nM full length PHD2.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Transplantation (AREA)
  • Obesity (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne les formes polymorphes du composé de Formule (I), une préparation de celles-ci comprenant la préparation d'intermédiaires et de compositions pharmaceutiques, et l'utilisation d'un polymorphe tel que mentionné ci-dessus dans le traitement d'une maladie, d'un trouble ou d'un état ou dans la fabrication d'un médicament pour le traitement d'une maladie, d'un trouble ou d'un état.
PCT/CN2012/079058 2011-07-22 2012-07-23 Formes polymorphes de composés en tant qu'inhibiteur de prolyle hydroxylase et leurs utilisations WO2013013609A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
US14/233,902 US9206134B2 (en) 2011-07-22 2012-07-23 Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof
EP12817360.6A EP2734504B1 (fr) 2011-07-22 2012-07-23 Formes polymorphes de composés en tant qu'inhibiteur de prolyle hydroxylase et leurs utilisations
JP2014520521A JP6099644B2 (ja) 2011-07-22 2012-07-23 プロリルヒドロキシラーゼ阻害剤としての化合物の多形体、およびその使用
CA2842730A CA2842730C (fr) 2011-07-22 2012-07-23 Formes polymorphes de composes en tant qu'inhibiteur de prolyle hydroxylase et leurs utilisations
KR1020147004452A KR102029951B1 (ko) 2011-07-22 2012-07-23 프로릴 히드록실라제 억제제로서 화합물의 다형체형, 및 이의 용도
ES12817360.6T ES2606631T3 (es) 2011-07-22 2012-07-23 Formas polimeróficas de compuestos como inhibidor de la prolila hidroxilasa, y usos de los mismos
AU2012289429A AU2012289429B2 (en) 2011-07-22 2012-07-23 Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof
CN201280036322.0A CN104024227B (zh) 2011-07-22 2012-07-23 抑制脯氨酸羟化酶活性的化合物的晶型及其应用
IL230580A IL230580B (en) 2011-07-22 2014-01-22 Polymorphic forms of compounds as prolyl hydroxylase inhibitors and their uses
ZA2014/01310A ZA201401310B (en) 2011-07-22 2014-02-20 Polymorphic forms of compounds as prolyl hydroxylase inhibitor,and uses thereof

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN201110207175.6 2011-07-22
CN201110207175 2011-07-22
CN201110209657 2011-07-25
CN201110209657.5 2011-07-25
CN201110211297.2 2011-07-26
CN201110211297 2011-07-26

Publications (1)

Publication Number Publication Date
WO2013013609A1 true WO2013013609A1 (fr) 2013-01-31

Family

ID=47600518

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2012/079058 WO2013013609A1 (fr) 2011-07-22 2012-07-23 Formes polymorphes de composés en tant qu'inhibiteur de prolyle hydroxylase et leurs utilisations

Country Status (11)

Country Link
US (1) US9206134B2 (fr)
EP (1) EP2734504B1 (fr)
JP (1) JP6099644B2 (fr)
KR (1) KR102029951B1 (fr)
CN (1) CN104024227B (fr)
AU (1) AU2012289429B2 (fr)
CA (1) CA2842730C (fr)
ES (1) ES2606631T3 (fr)
IL (1) IL230580B (fr)
WO (1) WO2013013609A1 (fr)
ZA (1) ZA201401310B (fr)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014014834A1 (fr) * 2012-07-16 2014-01-23 Fibrogen, Inc. Procédé de fabrication de composés isoquinoléine
CN103539735A (zh) * 2012-07-16 2014-01-29 菲布罗根有限公司 脯氨酰羟化酶抑制剂的晶体形态
CN103694172A (zh) * 2013-12-26 2014-04-02 辽宁亿灵科创生物医药科技有限公司 含氮杂芳基化合物的衍生物
US8883823B2 (en) 2012-07-16 2014-11-11 Fibrogen, Inc. Crystalline forms of a prolyl hydroxylase inhibitor
WO2015073779A1 (fr) * 2013-11-15 2015-05-21 Akebia Therapeutics, Inc. Formes solides d'acide {[5-(3-chlorophényl)-3-hydroxypyridine-2-carbonyl] amino}acétique, compositions et leurs utilisations
WO2016118858A1 (fr) * 2015-01-23 2016-07-28 Akebia Therapeutics, Inc. Formes solides d'acide 2-(5-(3-fluorophényl)-3-hydroxypicolinamido)acétique, compositions et utilisation dudit acide
EP3305769A1 (fr) 2016-10-07 2018-04-11 Zentiva K.S. Procédé de préparation de (7-phénoxy-4-hydroxy-1-méthyl-isoquinoléine-3-carbonyl)-glycine (roxadustat) et ses intermédiaires sur la base de l'ouverture simultanée du cycle oxazolique, de la fission d'éther et de la création d'imine
CN108424388A (zh) * 2018-04-19 2018-08-21 杭州科巢生物科技有限公司 一种慢性贫血药物的制备方法
EP3275881A4 (fr) * 2015-03-27 2018-09-12 Shenyang Sunshine Pharmaceutical Co., Ltd. Composé de 5-hydroxyle-1,7-naphtyridine substitué par un groupe aryloxy ou hétérooxy, son procédé de préparation et son utilisation pharmaceutique
US10092558B2 (en) 2003-06-06 2018-10-09 Fibrogen, Inc. Nitrogen-containing heteroaryl compounds and methods of use thereof
US10246416B2 (en) 2011-06-06 2019-04-02 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides
WO2019106621A1 (fr) * 2017-12-01 2019-06-06 Dr. Reddy's Laboratories Limited Procédé de préparation de roxadustat et de ses intermédiaires
US10765672B2 (en) 2013-06-06 2020-09-08 Fibrogen, Inc. Pharmaceutical formulations of a HIF hydroxylase inhibitor
US10889546B2 (en) 2015-10-09 2021-01-12 Jiangsu Hengrui Medicine Co., Ltd. Alkynyl pyridine prolyl hydroxylase inhibitor, and preparation method and medical use thereof
WO2021077994A1 (fr) 2019-10-22 2021-04-29 苏州科睿思制药有限公司 Forme cristalline d'un inhibiteur de la prolyle hydroxylase du facteur inductible par hypoxie
WO2021252295A1 (fr) 2020-06-13 2021-12-16 Suzhou Pengxu Pharmatech Co., Ltd. Procédé de fabrication de roxadustat
US11324734B2 (en) 2015-04-01 2022-05-10 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
CN115144480A (zh) * 2021-03-31 2022-10-04 成都倍特药业股份有限公司 一种从罗沙司他中间体中检测吗啉和/或四甲基甲烷二胺的方法
US11524939B2 (en) 2019-11-13 2022-12-13 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid
US11713298B2 (en) 2018-05-09 2023-08-01 Akebia Therapeutics, Inc. Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid
US11857543B2 (en) 2013-06-13 2024-01-02 Akebia Therapeutics, Inc. Compositions and methods for treating anemia

Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104910113B (zh) * 2015-05-21 2017-05-10 中国科学院宁波材料技术与工程研究所 一种羟基苯酐的制备方法
CN104892509B (zh) * 2015-06-04 2018-03-09 苏州明锐医药科技有限公司 诺得司他的制备方法
CN108367017A (zh) * 2015-08-13 2018-08-03 索马根尼科斯公司 用于伤口愈合的短小发夹rna与微rna的组合物以及方法
CN106916105A (zh) * 2015-12-28 2017-07-04 徐州万邦金桥制药有限公司 一种纯化可博美的方法
CN106187888A (zh) * 2016-07-18 2016-12-07 江苏德源药业股份有限公司 Fg‑4592单晶及其制备方法
CN107954931B (zh) * 2016-10-17 2021-06-22 上海医药集团青岛国风药业股份有限公司 一种诺得司他的制备方法
CN108017583B (zh) * 2016-11-01 2021-04-06 徐州万邦金桥制药有限公司 一种可博美的制备方法
WO2019030711A1 (fr) * 2017-08-11 2019-02-14 Dr. Reddy’S Laboratories Limited Polymorphes et co-cristaux de roxadustat
US11192860B2 (en) * 2017-09-04 2021-12-07 Sandoz Ag Co-crystal of an orally available HIF prolyl hydroxylase inhibitor
CN109956870A (zh) 2017-12-14 2019-07-02 南京卡文迪许生物工程技术有限公司 一种罗沙司他的合成方法及其中间体化合物
CN108059679B (zh) * 2017-12-27 2020-03-24 吉林大学 一种人源单链抗体及其应用
CN110218184B (zh) * 2018-03-01 2022-09-27 广东东阳光药业有限公司 诺德司他共晶及其制备方法
CN110272386B (zh) * 2018-03-16 2022-09-09 上海医药集团青岛国风药业股份有限公司 一种诺得司他的制备方法
CN110903242B (zh) * 2018-09-14 2023-05-12 四川科伦药物研究院有限公司 罗沙司他中间体的制备方法
CN109369525A (zh) * 2018-12-29 2019-02-22 安礼特（上海）医药科技有限公司 罗沙司它的新晶型及其制备方法
WO2020178847A1 (fr) 2019-03-01 2020-09-10 Mylan Laboratories Limited Co-cristal de roxadustat et de d-proline
CN109776415B (zh) * 2019-03-07 2020-11-17 福建南方制药股份有限公司 一种Roxadustat中间体的制备方法
WO2020214853A1 (fr) 2019-04-18 2020-10-22 Nikang Therapeutics, Inc. Dérivés de tétrahydro-1h-cyclopenta [cd] indène en tant qu'inhibiteurs du facteur 2 inductible par l'hypoxie (alpha)
CN109956901B (zh) * 2019-04-25 2022-09-06 南京正大天晴制药有限公司 异喹啉酮类化合物的制备方法
US20220340532A1 (en) 2019-08-07 2022-10-27 Teva Pharmaceuticals International Gmbh Processes for the preparation of roxadustat and intermediates thereof
CN112679428A (zh) * 2019-10-17 2021-04-20 罗欣药业(上海)有限公司 罗沙司他新晶型及其制备方法
CN112679429B (zh) * 2019-10-18 2023-05-05 上海迪赛诺化学制药有限公司 一种制备异喹啉酮类化合物的方法
CN112679431B (zh) * 2019-10-18 2023-05-05 上海迪赛诺化学制药有限公司 一种制备异喹啉酮类化合物的方法
CN112679430B (zh) * 2019-10-18 2023-05-05 上海迪赛诺化学制药有限公司 一种制备异喹啉酮类化合物的方法
WO2021073623A1 (fr) * 2019-10-18 2021-04-22 上海迪赛诺化学制药有限公司 Procédé de préparation de composés d'isoquinolinone
CN111205224B (zh) * 2020-04-22 2020-08-25 南京佰麦生物技术有限公司 一种罗沙司他水合物的晶型及其制备方法和应用
CN112500344B (zh) * 2020-11-18 2022-07-01 江苏豪森药业集团有限公司 罗沙司他晶型及其制备方法
CN112194624A (zh) * 2020-11-18 2021-01-08 江苏豪森药业集团有限公司 一种异喹啉类化合物的晶型及其制备方法
CN115724796A (zh) * 2021-08-26 2023-03-03 成都苑东生物制药股份有限公司 一种罗沙司他新晶型及其制备方法
WO2023095162A1 (fr) 2021-11-26 2023-06-01 Mylan Laboratories Limited Cocristal de roxadustat et de nicotinamide

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004108681A1 (fr) 2003-06-06 2004-12-16 Fibrogen, Inc. Composes heteroaryliques contenant de l'azote et leur utilisation dans l'augmentation de l'erythropoietine endogene
WO2006133391A2 (fr) 2005-06-06 2006-12-14 Fibrogen, Inc. Methode amelioree de traitement de l'anemie
WO2007070359A2 (fr) 2005-12-09 2007-06-21 Amgen Inc. Composes a base de quinolone presentant une activite inhibitrice de prolyle hydroxylase, et leurs compositions et utilisations
WO2007146438A1 (fr) 2006-06-15 2007-12-21 Fibrogen, Inc. Composés et procédés destinés au traitement prophylactique d'une anémie induite par un cancer
US20080004817A1 (en) 2006-06-30 2008-01-03 Akira Nishimizu Method and apparatus for evaluating length of defect in eddy current testing
WO2011006355A1 (fr) 2009-07-15 2011-01-20 Beijing Beta Pharma Inc. Composés utiles en tant que mimétiques d'hypoxie, et compositions, et utilisations associées

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5470285A (en) * 1977-11-14 1979-06-05 Tanabe Seiyaku Co Ltd Production of 4-hydroxyisocarbostyryl-3-carboxylic analog
DE19746287A1 (de) * 1997-10-20 1999-04-22 Hoechst Marion Roussel De Gmbh Substituierte Isochinolin-2-Carbonsäureamide, ihre Herstellung und ihre Verwendung als Arzneimittel
US7893071B2 (en) * 2001-04-23 2011-02-22 University Of Virginia Patent Foundation Synthesis and evaluation of novel phthalimide mimics as anti-angiogenic
US7189697B2 (en) 2004-04-13 2007-03-13 Trustees Of Tufts College Compositions and uses of a galectin for treatment of dry eye syndrome
JP5161793B2 (ja) * 2006-01-27 2013-03-13 フィブロジェン， インコーポレイテッド 低酸素症誘導因子（ｈｉｆ）を安定化するシアノイソキノリン化合物

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004108681A1 (fr) 2003-06-06 2004-12-16 Fibrogen, Inc. Composes heteroaryliques contenant de l'azote et leur utilisation dans l'augmentation de l'erythropoietine endogene
WO2006133391A2 (fr) 2005-06-06 2006-12-14 Fibrogen, Inc. Methode amelioree de traitement de l'anemie
CN101394843A (zh) * 2005-06-06 2009-03-25 菲布罗根公司 使用HIFα稳定剂的改进的贫血治疗
WO2007070359A2 (fr) 2005-12-09 2007-06-21 Amgen Inc. Composes a base de quinolone presentant une activite inhibitrice de prolyle hydroxylase, et leurs compositions et utilisations
WO2007146438A1 (fr) 2006-06-15 2007-12-21 Fibrogen, Inc. Composés et procédés destinés au traitement prophylactique d'une anémie induite par un cancer
CN101500569A (zh) * 2006-06-15 2009-08-05 菲布罗根公司 用于治疗癌症贫血的hif羟化酶抑制剂
US20080004817A1 (en) 2006-06-30 2008-01-03 Akira Nishimizu Method and apparatus for evaluating length of defect in eddy current testing
WO2011006355A1 (fr) 2009-07-15 2011-01-20 Beijing Beta Pharma Inc. Composés utiles en tant que mimétiques d'hypoxie, et compositions, et utilisations associées

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DAO JH ET AL., ANAL BIOCHEM., vol. 384, 2009, pages 213 - 23
HSIEH MM ET AL., BLOOD, vol. 110, 2007, pages 2140 - 7
ROBINSON A ET AL., GASTROENTEROLOGY, vol. 134, 2008, pages 145 - 55
See also references of EP2734504A4

Cited By (64)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10092558B2 (en) 2003-06-06 2018-10-09 Fibrogen, Inc. Nitrogen-containing heteroaryl compounds and methods of use thereof
US11229637B2 (en) 2003-06-06 2022-01-25 Fibrogen, Inc. Nitrogen-containing heteroaryl compounds and methods of use thereof
US10646482B2 (en) 2003-06-06 2020-05-12 Fibrogen, Inc. Nitrogen-containing heteroaryl compounds and methods of use thereof
US11267785B2 (en) 2011-06-06 2022-03-08 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids, esters and amides
US10738010B2 (en) 2011-06-06 2020-08-11 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides
US10246416B2 (en) 2011-06-06 2019-04-02 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides
CN109369524A (zh) * 2012-07-16 2019-02-22 菲布罗根有限公司 脯氨酰羟化酶抑制剂的晶体形态
CN103539735A (zh) * 2012-07-16 2014-01-29 菲布罗根有限公司 脯氨酰羟化酶抑制剂的晶体形态
US9340511B2 (en) 2012-07-16 2016-05-17 Fibrogen, Inc. Process for making isoquinoline compounds
US9371288B2 (en) 2012-07-16 2016-06-21 Fibrogen, Inc. Crystalline forms of a prolyl hydroxylase inhibitor
EP4029854A1 (fr) * 2012-07-16 2022-07-20 Fibrogen, Inc. Formes cristallines d'un inhibiteur de la prolyle hydroxylase
US10272078B2 (en) 2012-07-16 2019-04-30 Fibrogen, Inc. Crystalline forms of a prolyl hydroxylase inhibitor
US9617218B2 (en) 2012-07-16 2017-04-11 Fibrogen, Inc. Crystalline forms of a prolyl hydroxylase inhibitor
EP3470397B1 (fr) 2012-07-16 2021-12-29 Fibrogen, Inc. Formes cristallines d'un inhibiteur de la prolyle hydroxylase
US9708269B2 (en) 2012-07-16 2017-07-18 Fibrogen, Inc. Process for making isoquinoline compounds
CN103539735B (zh) * 2012-07-16 2017-08-04 菲布罗根有限公司 脯氨酰羟化酶抑制剂的晶体形态
AU2013290437B2 (en) * 2012-07-16 2017-11-02 Fibrogen, Inc. Process for making isoquinoline compounds
CN107382859A (zh) * 2012-07-16 2017-11-24 菲布罗根有限公司 脯氨酰羟化酶抑制剂的晶体形态
CN107382860A (zh) * 2012-07-16 2017-11-24 菲布罗根有限公司 脯氨酰羟化酶抑制剂的晶体形态
CN107501177A (zh) * 2012-07-16 2017-12-22 菲布罗根有限公司 脯氨酰羟化酶抑制剂的晶体形态
CN107540607A (zh) * 2012-07-16 2018-01-05 菲布罗根有限公司 脯氨酰羟化酶抑制剂的晶体形态
US9918977B2 (en) 2012-07-16 2018-03-20 Fibrogen, Inc. Crystalline forms of a prolyl hydroxylase inhibitor
KR102318720B1 (ko) 2012-07-16 2021-10-28 피브로겐, 인크. 프롤릴 하이드록실라제 억제제 [(4-하이드록시-1-메틸-7-페녹시-아이소퀴놀린-3-카보닐)-아미노]-아세트산의 결정형
KR20200102556A (ko) * 2012-07-16 2020-08-31 피브로겐, 인크. 프롤릴 하이드록실라제 억제제 [(4-하이드록시-1-메틸-7-페녹시-아이소퀴놀린-3-카보닐)-아미노]-아세트산의 결정형
KR102149380B1 (ko) 2012-07-16 2020-08-28 피브로겐, 인크. 프롤릴 하이드록실라제 억제제 [(4-하이드록시-1-메틸-7-페녹시-아이소퀴놀린-3-카보닐)-아미노]-아세트산의 결정형
EP2872488B1 (fr) 2012-07-16 2018-08-22 Fibrogen, Inc. Formes cristallines d'un inhibiteur de la prolyl hydroxylase
WO2014014835A3 (fr) * 2012-07-16 2014-08-21 Fibrogen, Inc. Formes cristallines d'un inhibiteur de la prolyl hydroxylase
KR20150058154A (ko) * 2012-07-16 2015-05-28 피브로겐, 인크. 프롤릴 하이드록실라제 억제제 [(4-하이드록시-1-메틸-7-페녹시-아이소퀴놀린-3-카보닐)-아미노]-아세트산의 결정형
US10118897B2 (en) 2012-07-16 2018-11-06 Fibrogen, Inc. Crystalline forms of a prolyl hydroxylase inhibitor
US8883823B2 (en) 2012-07-16 2014-11-11 Fibrogen, Inc. Crystalline forms of a prolyl hydroxylase inhibitor
US9115085B2 (en) 2012-07-16 2015-08-25 Fibrogen, Inc. Crystalline forms of a prolyl hydroxylase inhibitor
WO2014014834A1 (fr) * 2012-07-16 2014-01-23 Fibrogen, Inc. Procédé de fabrication de composés isoquinoléine
EP3470397A1 (fr) * 2012-07-16 2019-04-17 Fibrogen, Inc. Formes cristallines d'un inhibiteur de la prolyle hydroxylase
US10765672B2 (en) 2013-06-06 2020-09-08 Fibrogen, Inc. Pharmaceutical formulations of a HIF hydroxylase inhibitor
US11857543B2 (en) 2013-06-13 2024-01-02 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
WO2015073779A1 (fr) * 2013-11-15 2015-05-21 Akebia Therapeutics, Inc. Formes solides d'acide {[5-(3-chlorophényl)-3-hydroxypyridine-2-carbonyl] amino}acétique, compositions et leurs utilisations
US11065237B2 (en) 2013-11-15 2021-07-20 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US11690836B2 (en) 2013-11-15 2023-07-04 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US10149842B2 (en) 2013-11-15 2018-12-11 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
KR102495018B1 (ko) 2013-11-15 2023-02-06 아케비아 테라퓨틱스 인코포레이티드 ｛[5-(3-클로로페닐)-3-하이드록시피리딘-2-카보닐]아미노｝아세트산의 고체형, 이의 조성물 및 용도
US10596158B2 (en) 2013-11-15 2020-03-24 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US9701636B2 (en) 2013-11-15 2017-07-11 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
KR20220042498A (ko) * 2013-11-15 2022-04-05 아케비아 테라퓨틱스 인코포레이티드 ｛[5-(3-클로로페닐)-3-하이드록시피리딘-2-카보닐]아미노｝아세트산의 고체형, 이의 조성물 및 용도
CN105916502A (zh) * 2013-11-15 2016-08-31 阿克比治疗有限公司 {[5-(3-氯苯基)-3-羟基吡啶-2-羰基]氨基}乙酸的固体形式，其组合物和用途
US9987262B2 (en) 2013-11-15 2018-06-05 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
CN103694172A (zh) * 2013-12-26 2014-04-02 辽宁亿灵科创生物医药科技有限公司 含氮杂芳基化合物的衍生物
WO2016118858A1 (fr) * 2015-01-23 2016-07-28 Akebia Therapeutics, Inc. Formes solides d'acide 2-(5-(3-fluorophényl)-3-hydroxypicolinamido)acétique, compositions et utilisation dudit acide
US10150734B2 (en) 2015-01-23 2018-12-11 Akebia Therapeutics, Inc. Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof
EP3275881A4 (fr) * 2015-03-27 2018-09-12 Shenyang Sunshine Pharmaceutical Co., Ltd. Composé de 5-hydroxyle-1,7-naphtyridine substitué par un groupe aryloxy ou hétérooxy, son procédé de préparation et son utilisation pharmaceutique
US11324734B2 (en) 2015-04-01 2022-05-10 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
US11844756B2 (en) 2015-04-01 2023-12-19 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
US10889546B2 (en) 2015-10-09 2021-01-12 Jiangsu Hengrui Medicine Co., Ltd. Alkynyl pyridine prolyl hydroxylase inhibitor, and preparation method and medical use thereof
EP3305769A1 (fr) 2016-10-07 2018-04-11 Zentiva K.S. Procédé de préparation de (7-phénoxy-4-hydroxy-1-méthyl-isoquinoléine-3-carbonyl)-glycine (roxadustat) et ses intermédiaires sur la base de l'ouverture simultanée du cycle oxazolique, de la fission d'éther et de la création d'imine
WO2019106621A1 (fr) * 2017-12-01 2019-06-06 Dr. Reddy's Laboratories Limited Procédé de préparation de roxadustat et de ses intermédiaires
EP3717456A4 (fr) * 2017-12-01 2021-09-15 Dr. Reddy's Laboratories Limited Procédé de préparation de roxadustat et de ses intermédiaires
CN108424388A (zh) * 2018-04-19 2018-08-21 杭州科巢生物科技有限公司 一种慢性贫血药物的制备方法
US12269802B2 (en) 2018-05-09 2025-04-08 Akebia Therapeutics, Inc. Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino] acetic acid
US11713298B2 (en) 2018-05-09 2023-08-01 Akebia Therapeutics, Inc. Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid
WO2021077994A1 (fr) 2019-10-22 2021-04-29 苏州科睿思制药有限公司 Forme cristalline d'un inhibiteur de la prolyle hydroxylase du facteur inductible par hypoxie
EP4049999A4 (fr) * 2019-10-22 2023-04-19 Crystal Pharmaceutical (Suzhou) Co., Ltd. Forme cristalline d'un inhibiteur de la prolyle hydroxylase du facteur inductible par hypoxie
US11524939B2 (en) 2019-11-13 2022-12-13 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid
WO2021252295A1 (fr) 2020-06-13 2021-12-16 Suzhou Pengxu Pharmatech Co., Ltd. Procédé de fabrication de roxadustat
CN115144480B (zh) * 2021-03-31 2023-11-28 成都倍特药业股份有限公司 一种从罗沙司他中间体中检测吗啉和/或四甲基甲烷二胺的方法
CN115144480A (zh) * 2021-03-31 2022-10-04 成都倍特药业股份有限公司 一种从罗沙司他中间体中检测吗啉和/或四甲基甲烷二胺的方法

Also Published As

Publication number Publication date
JP6099644B2 (ja) 2017-03-22
EP2734504B1 (fr) 2016-09-14
JP2014524920A (ja) 2014-09-25
EP2734504A1 (fr) 2014-05-28
CA2842730C (fr) 2018-08-21
ZA201401310B (en) 2015-04-29
KR102029951B1 (ko) 2019-11-08
IL230580B (en) 2019-07-31
AU2012289429A1 (en) 2014-03-20
KR20140049004A (ko) 2014-04-24
AU2012289429B2 (en) 2016-07-28
CN104024227B (zh) 2015-12-02
ES2606631T3 (es) 2017-03-24
US9206134B2 (en) 2015-12-08
US20150031721A1 (en) 2015-01-29
CA2842730A1 (fr) 2013-01-31
IL230580A0 (en) 2014-03-31
EP2734504A4 (fr) 2014-12-31
CN104024227A (zh) 2014-09-03

Similar Documents

Publication Publication Date Title
US9206134B2 (en) Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof
WO2022138988A1 (fr) Dérivé de triazine ayant un effet inhibiteur sur la propagation de virus, et composition pharmaceutique le contenant
Yaseen et al. Pyridazinone substituted benzenesulfonamides as potent carbonic anhydrase inhibitors
JP2016145212A (ja) Ｃｄｄｏエチルエステルの多形体及びその用途
CA2767911C (fr) Composes utiles en tant que mimetiques d'hypoxie, et compositions, et utilisations associees
JP2014534208A5 (fr)
US20220401419A1 (en) Hydrogen peroxide-responsive keap1-nrf2 ppi inhibitor prodrug, and preparation method therefor
US9238637B2 (en) Stable polymorphic forms of compound as hypoxia mimetics, and uses thereof
TWI582078B (zh) 抑制脯氨酸羥化酶活性的化合物的晶型及其應用
TW201736373A (zh) 作為免疫調節劑的三並環化合物
TWI424842B (zh) 含取代基的雜環化合物、包括其的藥物組合物，以及該化合物的應用
WO2023192864A2 (fr) Inhibiteurs de parp16 covalents
TW201321361A (zh) 抑制脯氨酸羥化酶活性的化合物的穩定晶型及其應用
CN116903556A (zh) 一种不可逆的hdac6亚型选择性抑制剂及其制备方法和应用
KR820000493B1 (ko) 퀴나졸린 유도체의 제조방법
CN110172052A (zh) 一种苯并吡喃酮衍生物的制备工艺与应用
JP2015163602A (ja) ［（４−ヒドロキシ−２−オキソ−１，２，５，６−テトラヒドロ−３−ピリジニル）カルボニル］グリシン化合物の結晶形及びそれらの製造方法
CA2940942A1 (fr) Polymorphes d'ester ethylique cddo et leurs utilisations

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12817360

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2014520521

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2842730

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20147004452

Country of ref document: KR

Kind code of ref document: A

REEP Request for entry into the european phase

Ref document number: 2012817360

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2012817360

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2012289429

Country of ref document: AU

Date of ref document: 20120723

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 14233902

Country of ref document: US

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载